An exciting area of opioid research is the regulation of long-term potentiation (LTP) by endogenous opioids. LTP is a form of synaptic plasticity used as a model of learning and memory. Understanding how opioids regulate LTP may reveal how opioids produce long term changes in behavior and influence learning. Numerous studies have indicated that endogenous opioid peptides regulate LTP of excitatory synaptic transmission in the hippocampal formation. This project will address an entirely new regulatory role of endogenous opioids in LTP. It appears that endogenous opioids can not only enhance LTP of excitation, but can also suppress LTP in inhibitory circuitry. Under normal circumstances, tetanic stimulation of the lateral perforant path (LPP) input to the dentate granule cells (DGCs) produces LTP of excitatory postsynaptic currents (EPSCs). However, LTP induction in the presence of either naloxone or the delta specific opioid antagonist, naltrindole, reveals robust and NMDA (N- methyl-D-aspartate) receptor dependent potentiation of polysynaptic feedforward GABAA inhibitory postsynaptic currents (IPSCs) recorded in DGCs. Our central hypothesis to explain the increased feedforward inhibition is that endogenous opioids might regulate LTP in interneurons. We propose that, under normal conditions, opioids released during tetanic stimulation of the LPP could hyperpolarize GABAergic interneurons and thereby reduce LTP of the LPP synapses driving the interneurons. Conversely, with delta opioid receptors blocked, LPP stimulation might more effectively depolarize interneurons, enabling LTP of their afferents. Our first goal will be to show that the potentiation of inhibition is due to LTP of excitatory synapses on interneurons, rather than due to LTP of GABAergic synapses on DOCs. To rule out LTP at GABAergic synapses on DGCs we will, l) Show that blocking calcium accumulation in DGCs during tetanic LPP stimulation does not block potentiation of the IPSC, and 2) Show that monosynaptic DGC IPSCs are not potentiated. To confirm that LTP of EPSCs occurs on GABAergic interneurons, we will, 3) voltage clamp identified interneurons and measure EPSCs before and after LPP tetanization. Our second goal will be to explore mechanisms whereby endogenous opioids might regulate LTP of interneurons. Therefore, we will, 4) Determine if endogenous opioids can hyperpolarize interneurons, and 5) Determine the effects of applied opioid agonists on interneuron membrane currents.